The present invention relates to compounds that are inhibitors of the microsomal triglyceride transfer protein. The invention also relates to methods of treatment of atherosclerosis, obesity, restenosis, coronary heart disease, hyperlipoproteinemia, hypercholesterolemia, and hypertriglyceridemia, and to pharmaceutical compositions containing the inhibitors.
The microsomal triglyceride transfer protein (MTP) is required for the assembly of lipoproteins containing apolipoprotein B (apoB). Examples of lipoproteins that contain apoB, include chylomicrons, very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), high density lipoproteins (HDL), low density lipoproteins (LDL), and lipoprotein a [Lp(a)]. MTP is a heterodimer composed of a unique large subunit of 97 kDA and an ubiquitous multifunctional protein called protein disulfide isomerase.
The function of MTP has been discovered, in part, through the investigation of the disease abetalipoproteinemia, which is a rare autosomal recessive disease that is characterized by defective apoB lipoprotein assembly and secretion. Studies have now shown that persons having abetalipoproteinemia have mutations in the MTP large subunit gene. As a result of this mutation, persons afflicted with abetalipoproteinemia have only trace levels of apoB in plasma and total plasma levels of cholesterol of about 40 mg/dL.
Abnormal plasma lipid and/or lipoprotein concentrations plays a role in diseases such as atherosclerosis, obesity, restenosis, coronary heart disease, hyperlipoproteinemia, hypercholesterolemia, and hypertriglyceridemia. Thus, it would be beneficial to obtain compounds that can inhibit MTP.
U.S. Pat. Nos. 5,712,279 and 5,739,135, which are hereby incorporated by reference in their entirety, relate to compounds that inhibit MTP. The compounds disclosed in these patents are structurally different from the compounds of the present invention.
The present invention provides compounds having the Formula I 
wherein
R1 is pyridyl, xe2x80x94CH2-pyridyl, substituted pyridyl, xe2x80x94CH2-substituted pyridyl, phenyl, substituted phenyl, 
each Ra and Rb are independently hydrogen or C1-C6 alkyl;
m is 0 to 4;
n is 0, 1, or 2;
R2 is substituted phenyl, phenyl, 
xe2x80x83phenyl or substituted phenyl, a pharmaceutically acceptable salt thereof.
In a preferred embodiment of the compounds of Formula I, 
In another preferred embodiment of the compounds of Formula I,
R3 is 
In another preferred embodiment of the compounds of Formula I, R1 is pyridyl, or xe2x80x94CH2-pyridyl.
In another preferred embodiment of the compounds of Formula I, R1 is substituted phenyl or substituted pyridyl.
In another preferred embodiment of the compounds of Formula I, R2 is substituted phenyl, or phenyl.
In another preferred embodiment, the present invention provides compounds having the Formula I 
wherein
R1 is pyridyl, substituted phenyl, phenyl
xe2x80x83xe2x80x94CH2-pyridyl, 
xe2x80x83substituted pyridyl, or 
R2 is substituted phenyl, phenyl, 
xe2x80x83substituted phenyl, or the pharmaceutically acceptable salt thereof.
In a more preferred embodiment of the compounds of Formula I, the present invention provides the compounds:
2-Benzylsulfanyl-N-(4-methoxy-benzyl)-N-(4-methoxy-phenyl)-benzamide;
N-(3,5-Di-tert-butyl-benzyl)-3,4-dimethoxy-N-phenyl-benzamide;
N-(3,5-Bis-trifluoromethyl-benzyl)-3,4-dimethoxy-N-phenyl-benzamide;
N-(3,5-Dibromo-benzyl)-3,4-dimethoxy-N-phenyl-benzamide;
3,4-Dimethoxy-N-(4-methoxy-benzyl)-N-phenyl-benzamide;
3,4-Dimethoxy-N-(3-methoxy-benzyl)-N-phenyl-benzamide;
N-(3,4-Dichloro-benzyl)-3,4-dimethoxy-N-phenyl-benzamide;
3,4-Dimethoxy-N-naphthalen-2-ylmethyl-N-phenyl-benzamide;
N-(4-tert-Butyl-benzyl)-3,4-dimethoxy-N-phenyl-benzamide; or
N-Biphenyl-2-ylmethyl-3,4-dimethoxy-N-phenyl-benzamide.
In a more preferred embodiment of the compounds of Formula I, the present invention provides the compounds:
N-(3,4-Dichloro-benzyl)-N-(2-methoxy-phenyl)-benzamide;
N-(3,5-Di-tert-butyl-benzyl)-N-[4-(3-diethylamino-propyl)-phenyl]-benzamide;
N-(3,5-Bis-trifluoromethyl-benzyl)-N-[4-(3-diethylamino-propyl)-phenyl]-benzamide;
N-(3,5-Dibromo-benzyl)-N-[4-(3-diethylamino-propyl)-phenyl]-benzamide;
N-[4-(3-Diethylamino-propyl)-phenyl]-N-(4-methoxy-benzyl)-benzamide;
N-[4-(3-Diethylamino-propyl)-phenyl]-N-(3-methoxy-benzyl)-benzamide;
N-(3,4-Dichloro-benzyl)-N-[4-(3-diethylamino-propyl)-phenyl]-benzamide;
N-[4-(3-Diethylamino-propyl)-phenyl]-N-naphthalen-2-ylmethyl-benzamide;
N-Biphenyl-2-ylmethyl-N-[4-(3-diethylamino-propyl)-phenyl]-benzamide; or
3-Methyl-thiophene-2-carboxylic acid (4-iodo-phenyl)-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-amide.
In a more preferred embodiment of the compounds of Formula I, the present invention provides the compounds:
N-(4-Methoxy-benzyl)-N-phenyl-benzamide;
N-(3-Methoxy-benzyl)-N-phenyl-benzamide;
3,4,5-Trimethoxy-N-naphthalen-2-ylmethyl-N-quinolin-3-yl-benzamide;
N-(4-tert-Butyl-benzyl)-3,4,5-trimethoxy-N-quinolin-3-yl-benzamide;
N-Biphenyl-2-ylmethyl-3,4,5-trimethoxy-N-quinolin-3-yl-benzamide;
3,4,5-Trimethoxy-N-(6-methoxy-pyridin-3-yl)-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-benzamide;
N-(3,5-Di-tert-butyl-benzyl)-3,4,5-trimethoxy-N-(6-methoxy-pyridin-3-yl)-benzamide;
N-(3,4-Dichloro-benzyl)-3,4,5-trimethoxy-N-(6-methoxy-pyridin-3-yl)-benzamide;
4-Isopropyl-N-pyridin-3-yl-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-benzamide; or
4-Isopropyl-N-(3-methoxy-benzyl)-N-pyridin-3-yl-benzamide.
In a more preferred embodiment of the compounds of Formula I, the present invention provides the compounds:
4-Isopropyl-N-naphthalen-2-ylmethyl-N-pyridin-3-yl-benzamide;
xe2x80x2N-(4-tert-Butyl-benzyl)-4-isopropyl-N-pyridin-3-yl-benzamide;
N-Biphenyl-2-ylmethyl-4-isopropyl-N-pyridin-3-yl-benzamide;
2-Ethoxy-N-pyridin-3-yl-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-benzamide;
N-(3,5-Di-tert-butyl-benzyl)-2-ethoxy-N-pyridin-3-yl-benzamide;
N-(3,5-Dibromo-benzyl)-2-ethoxy-N-pyridin-3-yl-benzamide;
2-Ethoxy-N-(4-methoxy-benzyl)-N-pyridin-3-yl-benzamide;
2-Ethoxy-N-(3-methoxy-benzyl)-N-pyridin-3-yl-benzamide;
N-(3,4-Dichloro-benzyl)-2-ethoxy-N-pyridin-3-yl-benzamide; or
2-Ethoxy-N-naphthalen-2-ylmethyl-N-pyridin-3-yl-benzamide.
In a more preferred embodiment of the compounds of Formula I, the present invention provides the compounds:
N-(4-tert-Butyl-benzyl)-2-ethoxy-N-pyridin-3-yl-benzamide;
N-Biphenyl-2-ylmethyl-2-ethoxy-N-pyridin-3-yl-benzamide;
N-(6-Butoxy-pyridin-3-yl)-2-diethylamino-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-acetamide;
N-(6-Butoxy-pyridin-3-yl)-N-(4-tert-butyl-benzyl)-2-diethylamino-acetamide;
xe2x80x2N-Biphenyl-2-ylmethyl-N-(6-butoxy-pyridin-3-yl)-2-diethylamino-acetamide;
N-(2-Methoxy-phenyl)-N-naphthalen-2-ylmethyl-benzamide;
N-(4-Methoxy-benzyl)-N-(2-methoxy-phenyl)-benzamide;
N-(3-Methoxy-benzyl)-N-(2-methoxy-phenyl)-benzamide;
N-Biphenyl-2-ylmethyl-N-(2-methoxy-phenyl)-benzamide; or
N-[4-(3-Diethylamino-propyl)-phenyl]-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-benzamide.
In a more preferred embodiment of the compounds of Formula I, the present invention provides the compounds:
N-Biphenyl-2-ylmethyl-2-ethoxy-N-(6-methoxy-pyridin-3-yl)-benzamide;
N-Biphenyl-2-ylmethyl-2-methoxy-N-(6-methoxy-pyridin-3-yl)-benzamide;
N-Biphenyl-2-ylmethyl-2-methoxy-N-pyridin-3-ylmethyl-benzamide;
Benzo[b]thiophene-2-carboxylic acid biphenyl-2-ylmethyl-pyridin-4-yl-amide;
N-Biphenyl-2-ylmethyl-N-(6-methoxy-pyridin-3-yl)-2-nitro-benzamide;
N-Biphenyl-2-ylmethyl-4-ethoxy-N-(6-methoxy-pyridin-3-yl)-benzamide;
N-Biphenyl-2-ylmethyl-2-ethoxy-N-pyridin-3-ylmethyl-benzamide;
Benzo [1,3]dioxole-4-carboxylic acid biphenyl-2-ylmethyl-pyridin-3-ylmethyl-amide;
N-Biphenyl-2-ylmethyl-2-bromo-N-pyridin-3-ylmethyl-benzamide; or
3-Chloro-benzo [b]thiophene-2-carboxylic acid biphenyl-2-ylmethyl-pyridin-3-ylmethyl-amide.
In a more preferred embodiment of the compounds of Formula I, the present invention provides the compounds:
N-Biphenyl-2-ylmethyl-2-nitro-N-pyridin-3-ylmethyl-benzamide;
2-Benzyloxy-N-biphenyl-2-ylmethyl-N-pyridin-3-ylmethyl-benzamide;
N-Biphenyl-2-ylmethyl-4-ethoxy-N-pyridin-3-ylmethyl-benzamide;
N-Biphenyl-2-ylmethyl-4-methoxy-N-(4-methoxy-phenyl)-benzamide;
N-Biphenyl-2-ylmethyl-2-ethoxy-N-(4-methoxy-phenyl)-benzamide;
Benzo[1,3]dioxole-5-carboxylic acid biphenyl-2-ylmethyl-(4-methoxy-phenyl)-amide;
N-Biphenyl-2-ylmethyl-2,4-dimethoxy-N-(4-methoxy-phenyl)-benzamide;
2-Benzyloxy-N-biphenyl-2-ylmethyl-N-(4-methoxy-phenyl)-benzamide;
N-Biphenyl-2-ylmethyl-2-bromo-N-(4-methoxy-phenyl)-benzamide; or
Benzo[1,3]dioxole-4-carboxylic acid biphenyl-2-ylmethyl-(6-methoxy-pyridin-3-yl)-amide.
In a more preferred embodiment of the compounds of Formula I, the present invention provides the compounds:
N-Biphenyl-2-ylmethyl-2-ethoxy-N-pyridin-2-yl-benzamide;
N-Biphenyl-2-ylmethyl-2-bromo-N-pyridin-2-yl-benzamide;
N-Biphenyl-2-ylmethyl-2-nitro-N-pyridin-2-yl-benzamide;
2-Benzyloxy-N-biphenyl-2-ylmethyl-N-pyridin-2-yl-benzamide;
N-Biphenyl-2-ylmethyl-2-bromo-N-pyridin-3-yl-benzamide;
3-Chloro-benzo[b]thiophene-2-carboxylic acid biphenyl-2-ylmethyl-pyridin-3-yl-amide;
Benzo[b]thiophene-2-carboxylic acid biphenyl-2-ylmethyl-pyridin-3-yl-amide;
N-Biphenyl-2-ylmethyl-2-nitro-N-pyridin-3-yl-benzamide;
N-Biphenyl-2-ylmethyl-2-ethoxy-N-pyridin-4-yl-benzamide; or
N-Biphenyl-2-ylmethyl-2-methoxy-N-pyridin-4-yl-benzamide.
In a more preferred embodiment of the compounds of Formula I, the present invention provides the compounds:
Benzo[1,3]dioxole-4-carboxylic acid biphenyl-2-ylmethyl-pyridin-4-yl-amide;
N-Biphenyl-2-ylmethyl-2-bromo-N-pyridin-4-yl-benzamide;
N-Biphenyl-2-ylmethyl-2-nitro-N-pyridin-4-yl-benzamide;
2-Benzyloxy-N-biphenyl-2-ylmethyl-N-pyridin-4-yl-benzamide;
N-Biphenyl-2-ylmethyl-4-ethoxy-N-pyridin-4-yl-benzamide;
Benzo[b]thiophene-2-carboxylic acid biphenyl-2-ylmethyl-pyridin-3-ylmethyl-amide;
N-Biphenyl-2-ylmethyl-N-(4-methoxy-phenyl)-2-methylsulfanyl-benzamide;
N-Biphenyl-2-ylmethyl-2-isopropylsulfanyl-N-(4-methoxy-phenyl)-benzamide;
N-Biphenyl-2-ylmethyl-N-(3-methoxy-phenyl)-2-propylsulfanyl-benzamide; or
N-Biphenyl-2-ylmethyl-N-(3-methoxy-phenyl)-2-methylsulfanyl-benzamide.
In a more preferred embodiment of the compounds of Formula I, the present invention provides the compounds:
N-Biphenyl-2-ylmethyl-2-isopropylsulfanyl-N-(3-methoxy-phenyl)-benzamide;
2-Benzylsulfanyl-N-biphenyl-2-ylmethyl-N-(3-methoxy-phenyl)-benzamide;
2-Benzylsulfanyl-N-biphenyl-2-ylmethyl-N-(4-chloro-phenyl)-benzamide;
N-Biphenyl-2-ylmethyl-N-(3,4-dimethoxy-phenyl)-2-propylsulfanyl-benzamide;
N-Biphenyl-2-ylmethyl-N-(3,4-dimethoxy-phenyl)-2-methylsulfanyl-benzamide;
N-Biphenyl-2-ylmethyl-N-(3,4-dimethoxy-phenyl)-2-isopropylsulfanyl-benzamide;
N-Biphenyl-2-ylmethyl-N-(3,4-dimethoxy-phenyl)-3-phenylsulfanyl-benzamide;
2-Benzylsulfanyl-N-biphenyl-2-ylmethyl-N-(3,4-dimethoxy-phenyl)-benzamide;
xe2x80x2N-Biphenyl-2-ylmethyl-N-(4-methoxy-phenyl)-2-(propane-1-sulfinyl)-benzamide; or
xe2x80x2N-Biphenyl-2-ylmethyl-N-(4-methoxy-phenyl)-2-(propane-2-sulfinyl)-benzamide.
In a more preferred embodiment of the compounds of Formula I, the present invention provides the compounds:
xe2x80x22-Benzenesulfinyl-N-biphenyl-2-ylmethyl-N-(4-chloro-phenyl)-benzamide;
xe2x80x2N-Biphenyl-2-ylmethyl-N-(3,4-dimethoxy-phenyl)-2-(propane-1-sulfinyl)-benzamide;
N-Biphenyl-2-ylmethyl-N-(3,4-dimethoxy-phenyl)-2-(propane-2-sulfinyl)-benzamide; or
N-Biphenyl-2-ylmethyl-N-(3,4-dimethoxy-phenyl)-2-phenylmethanesulfinyl-.
Also provided is a pharmaceutical composition comprising a compound of Formula I.
Also provided is a method of treating atherosclerosis, the method comprising administering to a patient having or at risk of having atherosclerosis a therapeutically effective amount of a compound of Formula I.
Also provided is a method of treating restenosis, the method comprising administering to a patient having or at risk of having restenosis a therapeutically effective amount of a compound of Formula I.
Also provided is a method of treating coronary heart disease, the method comprising administering to a patient having or at risk of having coronary heart disease a therapeutically effective amount of a compound of Formula I.
Also provided is a method of treating hyperlipidemia, the method comprising administering to a patient having hyperlipidemia, a therapeutically effictive amount of a compound of Formula I.
Also provided is a method of treating hyperlipoproteinemia, the method comprising administering to a patient having hyperlipoproteinemia a therapeutically effective amount of a compound of Formula I.
Also provided is a method of treating hypercholesterolemia, the method of comprising administering to a patient having hyperchloesterolemia a therapeutically effective amount of a compound of Formula I.
Also provided is a method of treating hypertriglyceridemia, the method comprising administering to a patient having hypertriglyceridemia a therapeutically effective amount of a compound of Formula I.
Also provided is a method of treating obesity, the method of comprising administering to an obese patient a therapeutically effective amount of a compound of Formula I.
Also provided is a method of lowering plasma concentrations of apoB containing lipoproteins, the method comprising administering to a patient in need of lowering of apoB containing lipoproteins in plasma a therapeutically effective amount of a compound of Formula I.
Also provided is a method of lowering the plasma concentration of Lp(a) the method comprising administering to a patient in need of Lp(a) lowering a therapeutically effective amount of a compound of Formula I.
Also provided is a method of lowering the plasma concentration of LDL, the method comprising administering to a patient in need of LDL lowering a therapeutically effective amount of a compound of Formula I.
Also provided is a method of lowering the plasma concentration of triglycerides, the method comprising administering to a patient in need of triglyceride lowering a therapeutically effective amount of a compound of Formula I.
The term xe2x80x9calkylxe2x80x9d means a straight or branched hydrocarbon and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like. The alkyl group can also be substituted with one or more of the substituents listed below for aryl. Preferred alkyl groups have from 1 to 6 carbon atoms (C1-C6 alkyl).
The term xe2x80x9carylxe2x80x9d means an aromatic ring such as phenyl, 5-fluorenyl, 1-naphthyl, or 2-naphthyl, unsubstituted or substituted by 1 to 3 substituents selected from xe2x80x94C1-C6 alkyl, xe2x80x94OC1-C6 alkyl and xe2x80x94SC1-C6 alkyl, xe2x80x94OH, xe2x80x94SH, xe2x80x94F, xe2x80x94CN, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94CO2H, xe2x80x94CO2C1-C6 alkyl, 
xe2x80x94NH2, xe2x80x94NHC1-C6 alkyl, or xe2x80x94N(C1-C6alkyl)2.
The term xe2x80x9cpyridylxe2x80x9d means a radical given by the following formula: 
The line crossing the double bond indicates that the pyridyl group be attached by any carbon atom in the ring which is available. Preferrably, the pryidyl group is a 2-pyridyl group.
The term xe2x80x9csubstituted pyridylxe2x80x9d means a pyridyl wherein one to four substitutionally available positions are replaced by substituents selected from xe2x80x94C1-C6 alkyl, xe2x80x94OC1-C6 alkyl, xe2x80x94SC1-C6 alkyl, halogen, nitro, cyano xe2x80x94OH, xe2x80x94SH, xe2x80x94F, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94CO2H, xe2x80x94CO2C1-C6 alkyl, xe2x80x94NH2, 
xe2x80x94CONR8R9, xe2x80x94SO2alkyl, xe2x80x94SO2NH2, xe2x80x94NHC1-C6 alkyl, or xe2x80x94N(C1-C6alkyl)2. More preferably, the substituted pyridyl will have one to two substituents.
The term xe2x80x9csubstituted phenylxe2x80x9d means a phenyl wherein one to five substitutionally available positions are replaced by substituents selected from xe2x80x94C1-C6 alkyl, xe2x80x94OC1-C6 alkyl, xe2x80x94SC1-C6 alkyl, halogen, nitro, cyano xe2x80x94OH, xe2x80x94SH, xe2x80x94F, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94CO2H, xe2x80x94CO2C1-C6 alkyl, xe2x80x94NH2, 
xe2x80x94CONR8R9, xe2x80x94SO2alkyl, xe2x80x94SO2NH2, xe2x80x94NHC1-C6 alkyl, or xe2x80x94N(C1-C6alkyl)2. More preferably, the substituted phenyl will have one to two substituents.
The term xe2x80x9cheteroarylxe2x80x9d means an aromatic ring containing one or more heteroatoms. Examples of heteroaryl radicals include thienyl, furyl, pyrrolyl, thiazoyl, pyridyl, imidazolyl, or indolyl, substituted or unsubstituted by 1 or 2 substituents from the group of substituents described above for aryl. Examples of heteroatoms include nitrogen, oxygen, sulfur, and phosphorus.
The term xe2x80x9ccycloalkylxe2x80x9d means a saturated hydrocarbon ring, and includes for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, and the like. The cycloalkyl group can be substituted with from 1 to 3 substituents from the group of substituents described above for aryl.
The symbol xe2x80x9cxe2x80x94xe2x80x9d means a bond.
The term xe2x80x9cpatientxe2x80x9d means all animals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, pigs, rabbits, and rats.
A xe2x80x9ctherapeutically effective amountxe2x80x9d is an amount of a compound of the present invention that when administered to a patient ameliorates a symptom of atherosclerosis, obesity, coronary heart disease, restenosis hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, or lowers plasma levels of Lp(a), LDL, triglycerides VLDL, IDL chylomicrons or HDL. A therapeutically effective amount of a compound of the present invention can be easily determined by one skilled in the art by administering a quantity of a compound to a patient and observing the result. In addition, those skilled in the art are familiar with identifying patients having restenosis, coronary heart disease, atherosclerosis or who are at risk of having restenosis, coronary heart disease, atherosclerosis. Moreover, those skilled in the art are familiar with identifying patients having hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, or who are obese.
The term xe2x80x9cpharmaceutically acceptable salts, esters, amides, and prodrugsxe2x80x9d as used herein refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term xe2x80x9csaltsxe2x80x9d refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate and laurylsulphonate salts, and the like. These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. (See, for example, Berge S. M., et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. Pharm. Sci., 1977;66:1-19 which is incorporated herein by reference.)
Examples of pharmaceutically acceptable, non-toxic esters of the compounds of this invention include C1-C6 alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include C5-C7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. C1-C4 alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods.
Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary C1-C6 alkyl amines and secondary C1-C6 dialkyl amines wherein the alkyl groups are straight or branched chain. In the case of secondary amines the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C1-C3 alkyl primary amines and C1-C2 dialkyl secondary amines are preferred. Amides of the compounds of the invention may be prepared according to conventional methods.
The term xe2x80x9cprodrugxe2x80x9d refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, xe2x80x9cPro-drugs as Novel Delivery Systems,xe2x80x9d Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference.
The compounds of the present invention can be administered to a patient alone or as part of a composition that contains other components such as excipients, diluents, and carriers, all of which are well-known in the art. The compositions can be administered to humans and animals either orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically, locally (powders, ointments, or drops), or as a buccal or nasal spray.
Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, as for example, glycerol; (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarders, as for example paraffin; (f) absorption accelerators, as for example, quaternary ammonium compounds; (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate; (h) adsorbents, as for example, kaolin and bentonite; and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well-known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid esters of sorbitan or mixtures of these substances, and the like.
Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
The compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 2,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is preferable. However, the specific dosage used can vary. For example, the dosage can depended on a numbers of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well-known to those skilled in the art.
The compounds of the present invention can exist in different stereoisomeric forms by virtue of the presence of asymmetric centers in the compounds. It is contemplated that all stereoisomeric forms of the compounds as well as mixtures thereof, including racemic mixtures, form part of this invention.
In addition, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
The exemplified compounds of the present invention were synthesized using multiple parallel synthesis (combinatorial chemistry), but can also be prepared using standard laboratory scale organic reactions. It is also contemplated that compounds of the present invention may also be prepared through metabolism. It is intended that the scope of the application include compounds synthesized by any method known to those skilled in the art.
The examples presented below are intended to illustrate particular embodiments of the invention, and are not intended to limit the scope of the specification or the claims in any way.
Procedure 1
For Multiple, Simultaneous Solution Phase Synthesis
Combinatorial Chemistry
A blend of powdered bases was prepared as follows:
Sodium hydroxide pellets (3.2 g), anhydrous potassium carbonate (2.8 g) and tetrabutylammonium hydrogen sulfate (0.28 g) were ground together to give a uniform powder. The powder was stored under argon.
With regard to Table 1, a solution of reagent 2 (0.11 mmol) in toluene (1 mL) was added to reagent 1 (0.1 mmol) in a 2-dram glass vial. A blend of powered bases (described above) (0.04 g) was then added with a teflon-backed cap, and the reaction mixture was heated at 80xc2x0 C. and shaken on an orbital shaker for 2.5 hours. To the reaction mixture was added tris(2-aminioethyl)amine, polymer bound [Calbiochem-Novabiochem, San Diego, Calif.] (0.06 g). After 45 minutes at 80xc2x0 C., the reaction mixture was cooled to room temperature and shaken overnight. Dioxane (1.5 mL) added and silica gel (0.1 g) was added. The solids were removed by filtration and washed with dioxane (1.5 mL). The filtrate, collected in a tarred 2-dram vial, was concentrated to dryness. Further purification was achieved by partitioning between ethyl acetate and water. The organic phase was concentrated to dryness to yield the desired product.
The product was analyzed by liquid chromatography-mass spectrometry (LCMS). Conditions used for analytical work were an Alltech (Deerfield, Ill.), Alltima (Deerfield, Ill.), C18 column (150 mm ID, 4.6 mm length). The mobile phase (acetonitrile/water/0.05% trifluoroacetic acid at a flow of 1 mL/min) was used as a linear gradient of 50%-95% acetonitrile over 4 minutes then 95% acetonitrile over 9 minutes. Detection was at 214 nm. The compounds described in Table 1 were prepared simultaneously. The starting materials, called Reagents 1 and Reagents 2, are different for each individual compound synthesized and are described in Table 1. Reagents 1 and Reagents 2 are commercially available unless otherwise noted.
In general, the reagents can be obtained from Aldrich Chemical Company, Milwaukee, Wis.; Lancaster Synthesis Ltd., Lancaster, UK; or Fluka, Bucha, Switzerland.
Procedure 2
For Multiple, Simultaneous Solution Phase Synthesis.
With regard to Table 2, a solution of Reagent 3 (0.05 mmol) and a solution of pyridine (50 mmol) in dichloroethane (0.3 mL) were sequentially added to a glass 2-dram vial. A solution of Reagent 4 (0.1 mmol) in dichloroethane (0.5 mL) was added. The vial was sealed with a teflon-backed cap, and the reaction mixture was shaken on an orbital shaker for 4 days. Tris(2-aminioethyl)amine, polymer bound [Calbiochem-Novabiochem] (0.120 g) was added. After 2 hours the solids were removed by filtration washed with dichloromethane (2xc3x972 mL). The filtrate, collected in a tarred 2-dram vial, was concentrated to dryness.
Conditions used for analytical work were an Alltech, Alltima, C18 column (150 mm ID, 4.6 mm length). The mobile phase (acetonitrile/water/0.05% trifluoroacetic acid at a flow of 1 mL/minute) was used as a linear gradient of 50%-95% acetonitrile over 6 minutes, then 95% acetonitrile over 4 minutes, detection was at 214 nm. Conditions B used for analytical work were an Alltech, Alltima, C18 column (150 mm ID, 4.6 mm length). The mobile phase (acetonitrile/water/0.05% trifluoroacetic acid at a flow of 1 mL/minute) was used as a linear gradient of 50%-98% acetonitrile over 6.50 minutes, then 95% acetonitrile over 3.1 minutes, detection was at 214 nm.
The compounds described in Table 2 were prepared simultaneously. Reagents 3 and Reagents 4 are different for each individual compound and are described in Table 2. Reagents 3 are prepared as described herein. Reagents 4 are commercially available or prepared from the commercially available acid using oxalyl chloride and a catalytic amount of dimethylformamide (DMF) in dichloromethane unless otherwise noted.
Procedure 3
For Multiple, Simultaneous Solution Phase Synthesis
A solution of Reagent 3 (0.05 mm) and a solution of pyridine (5 mm) in dichloroethane (0.3 mL) were sequentially added by Tecan liquid handling robot to a glass 2 dram vial. A solution of Reagent 4 (0.1 mm) in dichloroethane (0.5 mL) was added by Tecan liquid handling robot. The vial was sealed with a teflon-backed cap, and the reaction mixture was shaken on an ISS orbital shaker for 4 days. Tris(2-aminioethyl)amine, polymer bound [Calbiochem-Novabiochem] (0.120 g) was added. After 2 hours the solids were removed by filtration through a Specdisk filter using a Tecan liquid handling robot to transfer the sample and washed with dichloromethane (2xc3x972 mL). The filtrate, collected in a tarred 2-dram vial, was concentrated to dryness by evaporation. The product was analyzed by LCMS. Conditions used for analytical work were an Alltech, Alltima, C 18 column (150 mm ID, 4.6 mm length). The mobile phase (acetonitrile/water/0.05% trifluoroacetic acid at a flow of 1 mL/min) was used as a linear gradient of 50%-95% acetonitrile over 6 minutes, then 95% acetonitrile over 4 minutes, detection was at 214 nm.
Further purification was achieved by reverse phase high-pressure liquid chromatography. Conditions used for preparative work were an Alltech, Alltima, C18 column (22 mm ID), 150 mm length). The mobile phase (acetonitrile/water/0.05% trifluoroacetic acid at a flow of 23 mL/min) was used as a linear gradient of 50%-98% acetonitrile over 12 minutes, detection was at 214 nm. Concentration of the appropriate fraction gave the title compound. Analysis of the product was by MS.
The compounds described in Table 3 were prepared simultaneously. Reagents 5 and Reagents 6 are different for each individual compound and are described in Table 3. Reagents 5 are prepared as described herein. Reagents 6 are commercially available or prepared from the commercially available acid using oxalyl chloride and a catalytic amount of DMF in dichloromethane unless otherwise noted.
Procedure 4
For Multiple, Simultaneous Solution Phase Synthesis
A solution of Reagent 7 (0.05 mm) and a solution of pyridine (5 mm) in dichloroethane (0.3 mL) were sequentially added to a glass 2-dram vial. A solution of Reagent 8 (0.1 mm) in dichloroethane (0.5 mL) was added. The vial was sealed with a teflon-backed cap, and the reaction mixture was shaken on an orbital shaker for 4 days. Tris(2-aminioethyl)amine, polymer bound [Calbiochem-Novabiochem, San Diego, Calif.] (0.120 g) was added. After 2 hours the solids were removed by filtration and washed with dichloromethane (2xc3x972 mL). The filtrate, collected in a tarred 2-dram vial, was concentrated to dryness by evaporation. An amount of the product (0.03 mmol) was removed from each sample to be used in Procedure 5.
The product was analyzed by LCMS. Conditions used for analytical work were an Alltech, Alltima, C18 column (150 mm ID, 4.6 mm length). The mobile phase (acetonitrile/water/0.05% trifluoroacetic acid at a flow of 1 mL/min) was used as a linear gradient of 50%-98% acetonitrile over 5 minutes. Then 98% acetonitrile over 5 minutes, detection was at 214 nm. Further purification was achieved by reverse phase high-pressure liquid chromatography. Conditions used for preparative work were an Alltech, Alltima, C18 column (22 mm ID, 150 mm length). The mobile phase (acetonitrile/water/0.05% trifluoroacetic acid at a flow of 23 mL/min) was used as a linear gradient of 50%-98% acetonitrile over 12 minutes, detection was at 214 nm. Concentration of the appropriate fraction gave the title compound. Analysis of the product was by MS. The compounds described in Table 3 were prepared simultaneously. Reagents 7 and Reagents 8 are different for each individual compound and are described in Table 4. Reagents 7 are prepared as described herein. Reagents 8 are commercially available or prepared from a commercially available acid using oxalyl chloride and a catalytic amount of DMF.
Procedure 5
For Multiple, Simultaneous Solution Phase Synthesis
A solution of Reagent 9 (the unpurified products from Procedure 4) (0.03 mm) was split into a 2-dram glass vial. Tetrahydrofuran/water/methanol (2:1:1) (1 mL) was added together with sodium periodate (0.15 mm). The reaction mixture was stirred at room temperature overnight. The organic components were removed by evaporation and the aqueous phase extracted by ethyl acetate. The filtrate, collected in a tarred 2-dram vial, was concentrated to dryness by evaporation. The product was analyzed by LCMS. Conditions used for analytical work were an Alltech, Alltima, C18 column (150 mm ID, 4.6 mm length). The mobile phase (acetonitrile/water/0.05% trifluoroacetic acid at a flow of 1 ML/min) was used as a linear gradient of 50%-98% acetonitrile over 7.50 minutes then 98% acetonitrile over 2.10 minutes, detection was at 214 nm. Further purification was achieved by reverse phase high-pressure liquid chromatography. Conditions used for preparative work were an Alltech, Alltima, C18 column (22 mm ID, 150 mm length). The mobile phase (acetonitrile/water/0.05% trifluoroacetic acid at a flow of 23 mL/min) was used as a linear gradient of 50%-98% acetonitrile over 12 minutes, detection was at 214 nm. Concentration of the appropriate fraction gave the compounds listed in Table 5. Analysis of the product was by MS. The compounds described in Table 5 were prepared simultaneously.
Starting Materials for Combinatorial Chemistry